The Chemistry and Cancer Program (CCP) seeks to discover small molecule chemicals capable of either antagonizing or agonizing regulatory pathways relevant to human cancer. Research efforts in the CCP proceed from one of two directions, chemistry-to-biology or biology-to-chemistry. In the former case, the discovery process starts with a novel natural product that is cytotoxic to cancer cells. This molecule, and specific derivatives synthesized by organic chemists, is then subjected to biochemical, genetic or molecular biological studies aimed at resolving its precise mode of action. Alternatively, knowledge of a specific biological pathway relevant to human cancer prompts attempts to identify small chemical antagonists or agonists of the pathway. The latter path is prosecuted by high throughput drug screening, rafional peptidomimetics, or preparation of synthetic analojgs of biological metabolites. In this context, the current scientific program themes are: 1) Identifying the Molecular Targets of Novel Cytotoxic Agents. 2) Biochemical Dissection of Novel. Cancer Cell-Specific Pathways. 3) Smac mimetics and other means of perturbing apoptosis with synthetic chemicals. 4) Regulation and targeting of the hypoxia response pathway with small molecules. The long-term objective of the CCP is to discover